(-)-(--D-2-Aminopurine dioxolane (APD) and (-)-(-D-2-amino-6-chloropurine dioxolane (ACPD) are recently synthesized dioxolanylpurine nucleoside derivatives being developed as potential prodrugs for the antiviral nucleoside analogue (-)-(-D-dioxolane-guanine (DXG). In vitro, APD and ACPD are converted to DXG by xanthine oxidase and adenosine deaminase, respectively. The purpose of this study was to evaluate the preclinical pharmacokinetics of APD and ACPD, and their potential for generating sustained levels of the parent nucleoside DXG in rhesus monkeys following oral administration. Both nucleoside derivatives were rapidly absorbed with similar peak concentrations achieved within 1 h after administration. However, concentrations of APD were more markedly sustained than those of ACPD. Both prodrugs yielded DXG, but, significantly higher serum DXG concentrations and AUC values were observed following administration of APD. In addition, APD produce higher CSF concentratio ns of prodrug and DXG than did ACPD. Thus, the results of this pharmacokinetic study suggest that APD is likely to serve as a better prodrug of DXG, and should be considered for clinical trials for antiviral therapy against human immunodeficiency virus and hepatitis B virus.